Metabolic syndrome

Nature Reviews Disease Primers, Journal Year: 2024, Volume and Issue: 10(1)

Published: Oct. 17, 2024

Language: Английский

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Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism

Molecular Metabolism, Journal Year: 2024, Volume and Issue: 80, P. 101880 - 101880

Published: Jan. 11, 2024

Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this is fat mass, there also a lean similar to other approaches that induce calorie deficit. Targeting signaling pathways regulate skeletal muscle hypertrophy promising avenue preserve mass modulate body composition. Myostatin Activin A are TGFβ-like ligands signal via the activin type II receptors (ActRII) antagonize growth. Pre-clinical clinical studies demonstrate ActRII blockade induces reduces mass. In manuscript, we test hypothesis combined plus GLP-1 agonist will leading improvements skeletomuscular metabolic function enhanced loss. study, explore therapeutic potential bimagrumab, monoclonal antibody against ActRII, modify composition alone during induced by semaglutide diet-induced mice. Mechanistically, define specific role anabolic kinase Akt mediating hypertrophic effects inhibition vivo. Treatment mice with bimagrumab ∼10% increase while simultaneously decreasing Daily treatment potently decreased weight; included significant decrease both Combination led superior preserving despite reduced intake. drugs was associated improved outcomes, increased exercise performance. Deletion isoforms modestly reduced, but did not prevent, driven inhbition. Collectively, these data improves parameters deficit agonism existence Akt-independent supporting absence signaling.

Language: Английский

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Cellular mechanisms of incretin hormone secretion

Journal of Molecular Endocrinology, Journal Year: 2024, Volume and Issue: 72(4)

Published: Jan. 19, 2024

Enteroendocrine cells located along the gastrointestinal epithelium sense different nutrients/luminal contents that trigger secretion of a variety gut hormones with roles in glucose homeostasis and appetite regulation. The incretin glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) are involved regulation insulin secretion, appetite, food intake body weight after their nutrient-induced from gut. GLP-1 mimetics have been developed used treatment type 2 diabetes mellitus obesity. Modulating release endogenous intestinal may be promising approach for obesity without surgery. For reason, current understanding cellular mechanisms underlying hormone will focus this review. controlling depend on nature stimulus, involving signalling pathways including ion channels, nutrient transporters G-protein-coupled receptors.

Language: Английский

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Metabolic dysfunction-associated steatotic liver disease: heterogeneous pathomechanisms and effectiveness of metabolism-based treatment

The Lancet Diabetes & Endocrinology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

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Prognostic impact of glucagon-like peptide-1 receptor (GLP1R) expression on cancer survival and its implications for GLP-1R agonist therapy: an integrative analysis across multiple tumor types

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

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Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes

Diabetes Therapy, Journal Year: 2024, Volume and Issue: 15(5), P. 1069 - 1084

Published: April 4, 2024

The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic obesity and diabetes. Here we outline evolution incretin-based pharmacotherapy, from exendin-4 to multi-incretin hormone that look set be our next step toward curing diabetes obesity. We discuss multiagonists currently clinical trials improvement efficacy each new generation these drugs bring. success agents preclinical models suggests promising future for treatment metabolic diseases, with most recent glucose-dependent insulinotropic peptide receptor:glucagon-like 1 receptor:glucagon (GIPR:GLP-1R:GCGR) triagonists rivaling bariatric surgery. However, further research is needed fully understand how therapies exert their effect on body weight last section cover open questions about potential mechanisms multiagonist drugs, understanding gut–brain communication can leveraged achieve sustained loss without adverse effects.

Language: Английский

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GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells

Peptides, Journal Year: 2024, Volume and Issue: 175, P. 171179 - 171179

Published: Feb. 14, 2024

Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide (GIPR) are transmembrane receptors involved in insulin, glucagon somatostatin secretion from the pancreatic islet. Therapeutic targeting of GLP1R GIPR restores blood glucose levels part by influencing beta cell, alpha cell delta function. Despite importance incretin-mimetics for diabetes therapy, our understanding expression patterns signaling within islet remain incomplete. Here, we present evidence major types, before addressing pathway(s) engaged, as well their influence on survival While is largely a cell-specific marker islet, expressed cells, (possibly) cells. engage G

Language: Английский

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Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss type 2 diabetes (T2D) patients. Agonists which bind stimulate multiple receptors have shown particular promise. However, off target effects, including nausea diarrhoea, remain a complication using these agents, modified versions with optimized pharmacological profiles and/or biased signaling at the cognate are increasingly sought. Here, we describe synthesis properties molecule binds glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) (GLP-1R GIPR) enhance secretion. HISHS-2001 shows increased affinity GLP-1R, well tendency towards reduced internalization recycling this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. also displayed significantly greater bias cAMP generation β-arrestin recruitment compared In contrast, G αs was lower tirzepatide but higher GIPR. Administered obese hyperglycaemic db/db mice, circulating whilst lowering body HbA1c similar efficacy substantially doses. Thus, represents novel improved profile.

Language: Английский

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Mechanisms of Lipid‐Associated Macrophage Accrual in Metabolically Stressed Adipose Tissue

BioEssays, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 19, 2025

ABSTRACT Adipose tissue (AT) inflammation, a hallmark of the metabolic syndrome, is triggered by overburdened adipocytes sending out immune cell recruitment signals during obesity development. An AT landscape persistent throughout weight loss and regain constitutes an immune‐obesogenic memory that hinders long‐term management. Lipid‐associated macrophages (LAMs) are emerging as major players in diseased, inflamed tissues may be key contributors to obesogenic AT. Our previous study found LAM abundance increases with via intermittent fasting (IF) obese mice, which driven adipocyte p53 signalling. However, specific causing accumulation under IF remain unknown. In this piece, we hypothesise on range adipocyte‐secreted can harbor immune‐attractive features upon fasting/refeeding cycles. We highlight possible mechanisms including death signalling, matrikines, other damage‐associated molecular patterns (DAMPs), well adipo(‐cyto)kines, lipid mediators, metabolites, extracellular vesicles, epigenetic rewiring. Finally, consider how advances gleaned from preclinical models might translatable management humans. Thus, provide vantage points driving monocyte recruitment, polarisation towards LAMs, retention, harness therapeutic potential modulating levels impacting disease.

Language: Английский

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Type 2 Diabetes Mellitus: A Comprehensive Review of Pathophysiology, Comorbidities, and Emerging Therapies

Comprehensive physiology, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 1, 2025

ABSTRACT Humans are perhaps evolutionarily engineered to get deeply addicted sugar, as it not only provides energy but also helps in storing fats, which survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel‐good factor, they trigger secretion of serotonin dopamine brain, associated with reward sensation, uplifting mood general. However, when consumed excess, contributes imbalance, weight gain, obesity, leading onset a complex metabolic disorder, generally referred diabetes. Type 2 diabetes mellitus (T2DM) is one most prevalent forms diabetes, nearly affecting all age groups. T2DM clinically diagnosed cardinal sign chronic hyperglycemia (excessive sugar blood). Chronic hyperglycemia, coupled dysfunctions pancreatic β‐cells, insulin resistance, immune inflammation, further exacerbate pathology T2DM. Uncontrolled T2DM, major public health concern, significantly toward progression several micro‐ macrovascular diseases, such diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, cardiovascular including cancer. The current review discusses epidemiology, causative factors, pathophysiology, comorbidities, existing emerging therapies related It future roadmap for alternative drug discovery management

Language: Английский

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